Abstract
Introduction: Upregulated microtubule-associated serine/threonine kinase like (MASTL), a cell cycle kinase required for a progression through mitosis, expression has been associated to poor prognosis. This study aimed to investigate the clinical relevance of MASTL expression in oral squamous cell carcinoma (OSCC) and a possible mechanistic link with epithelial-mesenchymal transition (EMT). Methods: Immunohistochemical analysis of MASTL, E-cadherin, vimentin, and Smad7 was performed in paraffin-embedded tissue specimens from 148 OSCC patients. Results: Nuclear MASTL expression was detected in 115 (77.7%) OSCC specimens. High MASTL expression was significantly associated with the male gender, smoking habit, T stage, early clinical stage, and absence of vascular invasion. MASTL expression was inversely correlated with Smad7, whereas no association was observed with E-cadherin and vimentin. Patients harboring tumors with low MASTL expression exhibited a poorer overall survival. Smad7 expression was significantly related to reduced disease-specific and overall survival. High levels of MASTL expression were associated with better prognosis in T3 patients, N0 cases, and patients treated by surgery combined with radiotherapy and chemotherapy. Conclusion: The present study uncovers MASTL as a good prognostic factor in OSCC and a potential link with EMT via Smad7.
Journal Section:
Research Article
References
1.
Graillon
N
, Iocca
O
, Carey
RM
, Benjamin
K
, Cannady
SB
, Hartner
L
, et al. What has the National Cancer Database taught us about oral cavity squamous cell carcinoma
. Int J Oral Maxillofac Surg
. 2022
;51
(1
):10
–7
. 2.
Shah
J
, Patel
S
, Singh
B
Jatin shah’s head and neck surgery and oncology
. 4th ed. Maryland Heights, MI, USA
: Mosby
; 2019
; p. 245
–95
.3.
Sung
H
, Ferlay
J
, Siegel
RL
, Laversanne
M
, Soerjomataram
I
, Jemal
A
, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries
. CA Cancer J Clin
. 2021
;71
(3
):209
–49
. 4.
Torralba
MG
, Aleti
G
, Li
W
, Moncera
KJ
, Lin
YH
, Yu
Y
, et al. Oral microbial species and virulence factors associated with oral squamous cell carcinoma
. Microb Ecol
. 2021
;82
(4
):1030
–46
. 5.
Mortazavi
H
, Baharvand
M
, Mehdipour
M
. Oral potentially malignant disorders: an overview of more than 20 entities
. J Dent Res Dent Clin Dent Prospects
. 2014
;8
(1
):6
–14
.6.
Zanoni
DK
, Montero
PH
, Migliacci
JC
, Shah
JP
, Wong
RJ
, Ganly
I
, et al. Survival outcomes after treatment of cancer of the oral cavity (1985-2015)
. Oral Oncol
. 2019
;90
:115
–21
. 7.
Hanahan
D
, Weinberg
RA
. The hallmarks of cancer
. Cell
. 2000
;100
(1
):57
–70
. 8.
Marzec
K
, Burgess
A
. The oncogenic functions of MASTL kinase
. Front Cell Dev Biol
. 2018
;6
:162
. 9.
Gharbi-Ayachi
A
, Labbé
JC
, Burgess
A
, Vigneron
S
, Strub
JM
, Brioudes
E
, et al. The substrate of Greatwall kinase, Arpp19, controls mitosis by inhibiting protein phosphatase 2A
. Science
. 2010
;330
(6011
):1673
–7
. 10.
Mochida
S
, Maslen
SL
, Skehel
M
, Hunt
T
. Greatwall phosphorylates an inhibitor of protein phosphatase 2Α that is essential for mitosis
. Science
. 2010
;330
(6011
):1670
–3
. 11.
Vigneron
S
, Brioudes
E
, Burgess
A
, Labbé
JC
, Lorca
T
, Castro
A
. Greatwall maintains mitosis through regulation of PP2A
. EMBO J
. 2009
;28
(18
):2786
–93
. 12.
Peng
A
, Yamamoto
TM
, Goldberg
ML
, Maller
JL
. A novel role for greatwall kinase in recovery from DNA damage
. Cell Cycle
. 2010
;9
(21
):4364
–9
. 13.
Álvarez-Fernández
M
, Sánchez-Martínez
R
, Sanz-Castillo
B
, Gan
PP
, Sanz-Flores
M
, Trakala
M
, et al. Greatwall is essential to prevent mitotic collapse after nuclear envelope breakdown in mammals
. Proc Natl Acad Sci USA
. 2013
;110
(43
):17374
–9
. 14.
Rogers
S
, McCloy
RA
, Parker
BL
, Gallego-Ortega
D
, Law
AMK
, Chin
VT
, et al. MASTL overexpression promotes chromosome instability and metastasis in breast cancer
. Oncogene
. 2018
;37
(33
):4518
–33
. 15.
Fatima
I
, Barman
S
, Uppada
J
, Chauhan
S
, Rauth
S
, Rachagani
S
, et al. MASTL regulates EGFR signaling to impact pancreatic cancer progression
. Oncogene
. 2021
;40
(38
):5691
–704
. 16.
Kang
Y
, Massagué
J
. Epithelial-mesenchymal transitions: twist in development and metastasis
. Cell
. 2004
;118
(3
):277
–9
.17.
Zidar
N
, Boštjančič
E
, Malgaj
M
, Gale
N
, Dovšak
T
, Didanovič
V
. The role of epithelial-mesenchymal transition in squamous cell carcinoma of the oral cavity
. Virchows Arch
. 2018
;472
(2
):237
–45
. 18.
Stolfi
C
, Marafini
I
, De Simone
V
, Pallone
F
, Monteleone
G
. The dual role of Smad7 in the control of cancer growth and metastasis
. Int J Mol Sci
. 2013
;14
(12
):23774
–90
. 19.
Wei
W
, Hu-Jie
C
. Association of the infiltration of tumor-associated macrophages, expression of Smad7 protein and prognosis in oral squamous cell carcinoma
. Arch Oral Biol
. 2018
;95
:22
–9
. 20.
Zhuge
BZ
, Du
BR
, Meng
XL
, Zhang
YQ
. MASTL is a potential poor prognostic indicator in ER+ breast cancer
. Eur Rev Med Pharmacol Sci
. 2017
;21
(10
):2413
–20
.21.
Sun
XJ
, Li
YL
, Wang
LG
, Liu
LQ
, Ma
H
, Hou
WH
, et al. Mastl overexpression is associated with epithelial to mesenchymal transition and predicts a poor clinical outcome in gastric cancer
. Oncol Lett
. 2017
;14
(6
):7283
–7
. 22.
Marzec
K
, Burgess
A
. The oncogenic functions of MASTL kinase
. Front Cell Dev Biol
. 2018
;6
:162
. 23.
Wang
L
, Luong
VQ
, Giannini
PJ
, Peng
A
. Mastl kinase, a promising therapeutic target, promotes cancer recurrence
. Oncotarget
. 2014
;5
(22
):11479
–89
. 24.
Gouttia
OG
, Zhao
J
, Li
Y
, Zwiener
MJ
, Wang
L
, Oakley
GG
, et al. The MASTL-ENSA-PP2A/B55 axis modulates cisplatin resistance in oral squamous cell carcinoma
. Front Cell Dev Biol
. 2022
;10
:904719
. 25.
Lydiatt
WM
, Patel
SG
, Ridge
JA
, O’Sullivan
B
, Shah
JP
. Staging head and neck cancers
. In: AJCC cancer staging manual
. 8th ed. AG Switzerland, IL, USA
: Springer International Publishing
; 2017
. p. 55
–181
.26.
Wangmo
C
, Charoen
N
, Jantharapattana
K
, Dechaphunkul
A
, Thongsuksai
P
. Epithelial-mesenchymal transition predicts survival in oral squamous cell carcinoma
. Pathol Oncol Res
. 2020
;26
(3
):1511
–8
. 27.
Vera
J
, Lartigue
L
, Vigneron
S
, Gadea
G
, Gire
V
, Del Rio
M
, et al. Greatwall promotes cell transformation by hyperactivating AKT in human malignancies
. Elife
. 2015
;4
:e10115
. 28.
Álvarez-Fernández
M
, Sanz-Flores
M
, Sanz-Castillo
B
, Salazar-Roa
M
, Partida
D
, Zapatero-Solana
E
, et al. Therapeutic relevance of the PP2A-B55 inhibitory kinase MASTL/Greatwall in breast cancer
. Cell Death Differ
. 2018
;25
(5
):828
–40
.29.
Chai
AWY
, Lim
KP
, Cheong
SC
. Translational genomics and recent advances in oral squamous cell carcinoma
. Semin Cancer Biol
. 2020
;61
:71
–83
. 30.
Chow
LQM
. Head and neck cancer
. N Engl J Med
. 2020
;382
(1
):60
–72
. 31.
Colevas
AD
, Yom
SS
, Pfister
DG
, Spencer
S
, Adelstein
D
, Adkins
D
, et al. NCCN guidelines insights: head and neck cancers, version 1.2018
. J Natl Compr Canc Netw
. 2018
;16
(5
):479
–90
. 32.
D’Cruz
AK
, Vaish
R
, Dhar
H
. Oral cancers: current status
. Oral Oncol
. 2018
;87
:64
–9
. 33.
Dasari
S
, Tchounwou
PB
. Cisplatin in cancer therapy: molecular mechanisms of action
. Eur J Pharmacol
. 2014
;740
:364
–78
. 34.
Nagel
R
, Stigter-van Walsum
M
, Buijze
M
, van den Berg
J
, van der Meulen
IH
, Hodzic
J
, et al. Genome-wide siRNA screen identifies the radiosensitizing effect of downregulation of MASTL and FOXM1 in NSCLC
. Mol Cancer Ther
. 2015
;14
(6
):1434
–44
. 35.
Katsuno
Y
, Lamouille
S
, Derynck
R
. TGF-β signaling and epithelial-mesenchymal transition in cancer progression
. Curr Opin Oncol
. 2013
;25
(1
):76
–84
. 36.
Ocasio
CA
, Rajasekaran
MB
, Walker
S
, Le Grand
D
, Spencer
J
, Pearl
FM
, et al. A first generation inhibitor of human Greatwall kinase, enabled by structural and functional characterisation of a minimal kinase domain construct
. Oncotarget
. 2016
;7
(44
):71182
–97
. 37.
Luo
L
, Li
N
, Lv
N
, Huang
D
. SMAD7: a timer of tumor progression targeting TGF-β signaling
. Tumor Biol
. 2014
;35
(9
):8379
–85
. 38.
Wang
H
, Nie
L
, Wu
L
, Liu
Q
, Guo
X
. NR2F2 inhibits Smad7 expression and promotes TGF-β-dependent epithelial-mesenchymal transition of CRC via transactivation of miR-21
. Biochem Biophys Res Commun
. 2017
;485
(1
):181
–8
. 39.
Stolfi
C
, De Simone
V
, Colantoni
A
, Franzè
E
, Ribichini
E
, Fantini
MC
, et al. A functional role for Smad7 in sustaining colon cancer cell growth and survival
. Cell Death Dis
. 2014
;5
(2
):e1073
. 40.
Boulay
J
, Mild
G
, Lowy
A
, Reuter
J
, Lagrange
M
, Terracciano
L
, et al. SMAD7 is a prognostic marker in patients with colorectal cancer
. Int J Cancer
. 2003
;104
(4
):446
–9
. © 2025 S. Karger AG, Basel
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
2025
You do not currently have access to this content.
